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First-in-human PET quantification study of cerebral α4ß2* nicotinic acetylcholine receptors using the novel specific radioligand (-)-[(18)F]Flubatine.
Sabri, Osama; Becker, Georg-Alexander; Meyer, Philipp M; Hesse, Swen; Wilke, Stephan; Graef, Susanne; Patt, Marianne; Luthardt, Julia; Wagenknecht, Gudrun; Hoepping, Alexander; Smits, René; Franke, Annegret; Sattler, Bernhard; Habermann, Bernd; Neuhaus, Petra; Fischer, Steffen; Tiepolt, Solveig; Deuther-Conrad, Winnie; Barthel, Henryk; Schönknecht, Peter; Brust, Peter.
Afiliação
  • Sabri O; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany; Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, Philipp-Rosenthal-Straße 27, 04103 Leipzig, Germany. Electronic address: Osama.Sabri@medizin.uni-leipzig.de.
  • Becker GA; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
  • Meyer PM; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
  • Hesse S; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany; Integrated Research and Treatment Centre (IFB) Adiposity Diseases, University of Leipzig, Philipp-Rosenthal-Straße 27, 04103 Leipzig, Germany.
  • Wilke S; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
  • Graef S; Department of Psychiatry, University of Leipzig, Semmelweisstraße 10, 04103 Leipzig, Germany; Max-Planck-Institute for Human Cognitive and Brain Sciences, Stephanstraße 1a, 04103 Leipzig, Germany.
  • Patt M; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
  • Luthardt J; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
  • Wagenknecht G; Electronic Systems (ZEA-2), Central Institute for Engineering, Electronics and Analytics, Research Centre Juelich, Wilhelm-Johnen-Straße, 52428 Juelich, Germany.
  • Hoepping A; ABX Advanced Biochemical Compounds GmbH, Heinrich-Gläser-Straße 10, 01454 Radeberg, Germany.
  • Smits R; ABX Advanced Biochemical Compounds GmbH, Heinrich-Gläser-Straße 10, 01454 Radeberg, Germany.
  • Franke A; Clinical Trial Centre Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany.
  • Sattler B; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
  • Habermann B; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
  • Neuhaus P; Clinical Trial Centre Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany.
  • Fischer S; Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstraße 15, 04318 Leipzig, Germany.
  • Tiepolt S; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
  • Deuther-Conrad W; Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstraße 15, 04318 Leipzig, Germany.
  • Barthel H; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
  • Schönknecht P; Department of Psychiatry, University of Leipzig, Semmelweisstraße 10, 04103 Leipzig, Germany.
  • Brust P; Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstraße 15, 04318 Leipzig, Germany.
Neuroimage ; 118: 199-208, 2015 Sep.
Article em En | MEDLINE | ID: mdl-26037057
ABSTRACT
α4ß2* nicotinic receptors (α4ß2* nAChRs) could provide a biomarker in neuropsychiatric disorders (e.g., Alzheimer's and Parkinson's diseases, depressive disorders, and nicotine addiction). However, there is a lack of α4ß2* nAChR specific PET radioligands with kinetics fast enough to enable quantification of nAChR within a reasonable time frame. Following on from promising preclinical results, the aim of the present study was to evaluate for the first time in humans the novel PET radioligand (-)-[(18)F]Flubatine, formerly known as (-)-[(18)F]NCFHEB, as a tool for α4ß2* nAChR imaging and in vivo quantification. Dynamic PET emission recordings lasting 270min were acquired on an ECAT EXACT HR+ scanner in 12 healthy male non-smoking subjects (71.0±5.0years) following the intravenous injection of 353.7±9.4MBq of (-)-[(18)F]Flubatine. Individual magnetic resonance imaging (MRI) was performed for co-registration. PET frames were motion-corrected, before the kinetics in 29 brain regions were characterized using 1- and 2-tissue compartment models (1TCM, 2TCM). Given the low amounts of metabolite present in plasma, we tested arterial input functions with and without metabolite corrections. In addition, pixel-based graphical analysis (Logan plot) was used. The model's goodness of fit, with and without metabolite correction was assessed by Akaike's information criterion. Model parameters of interest were the total distribution volume VT (mL/cm(3)), and the binding potential BPND relative to the corpus callosum, which served as a reference region. The tracer proved to have high stability in vivo, with 90% of the plasma radioactivity remaining as untransformed parent compound at 90min, fast brain kinetics with rapid uptake and equilibration between free and receptor-bound tracer. Adequate fits of brain TACs were obtained with the 1TCM. VT could be reliably estimated within 90min for all regions investigated, and within 30min for low-binding regions such as the cerebral cortex. The rank order of VT by region corresponded well with the known distribution of α4ß2* receptors (VT [thalamus] 27.4±3.8, VT [putamen] 12.7±0.9, VT [frontal cortex] 10.0±0.8, and VT [corpus callosum] 6.3±0.8). The BPND, which is a parameter of α4ß2* nAChR availability, was 3.41±0.79 for the thalamus, 1.04±0.25 for the putamen and 0.61±0.23 for the frontal cortex, indicating high specific tracer binding. Use of the arterial input function without metabolite correction resulted in a 10% underestimation in VT, and was without important biasing effects on BPND. Altogether, kinetics and imaging properties of (-)-[(18)F]Flubatine appear favorable and suggest that (-)-[(18)F]Flubatine is a very suitable and clinically applicable PET tracer for in vivo imaging of α4ß2* nAChRs in neuropsychiatric disorders.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzamidas / Encéfalo / Receptores Nicotínicos / Compostos Bicíclicos Heterocíclicos com Pontes / Tomografia por Emissão de Pósitrons Tipo de estudo: Prognostic_studies Limite: Aged / Humans / Male / Middle aged Idioma: En Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Benzamidas / Encéfalo / Receptores Nicotínicos / Compostos Bicíclicos Heterocíclicos com Pontes / Tomografia por Emissão de Pósitrons Tipo de estudo: Prognostic_studies Limite: Aged / Humans / Male / Middle aged Idioma: En Ano de publicação: 2015 Tipo de documento: Article